Safety of CoronaVac and ChAdOx1 vaccines against SARS-CoV-2 in patients with rheumatoid arthritis: data from the Brazilian multicentric study safer.

BACKGROUND: Patients with immune-mediated rheumatic diseases (IMRDs) have been prioritized for COVID-19 vaccination to mitigate the infection severity risks. Patients with rheumatoid arthritis (RA) are at a high risk of severe COVID-19 outcomes, especially those under immunosuppression or with associated comorbidities. However, few studies have assessed the safety of the COVID-19 vaccine in patients with RA. OBJECTIVE: To evaluate the safety of vaccines against SARS-CoV-2 in patients with RA. METHODS: This data are from the study "Safety and Efficacy on COVID-19 Vaccine in Rheumatic Diseases," a Brazilian multicentric prospective phase IV study to evaluate COVID-19 vaccine in IMRDs in Brazil. Adverse events (AEs) in patients with RA of all centers were assessed after two doses of ChAdOx1 (Oxford/AstraZeneca) or CoronaVac (Sinovac/Butantan). Stratification of postvaccination AEs was performed using a diary, filled out daily and returned at the end of 28 days for each dose. RESULTS: A total of 188 patients with RA were include, 90% female. CoronaVac was used in 109 patients and ChAdOx1 in 79. Only mild AEs were observed, mainly after the first dose. The most common AEs after the first dose were pain at the injection (46,7%), headache (39,4%), arthralgia (39,4%), myalgia (30,5%) and fatigue (26,6%), and ChAdOx1 had a higher frequency of pain at the injection (66% vs 32 %, p < 0.001) arthralgia (62% vs 22%, p < 0.001) and myalgia (45% vs 20%, p < 0.001) compared to CoronaVac. The more common AEs after the second dose were pain at the injection (37%), arthralgia (31%), myalgia (23%), headache (21%) and fatigue (18%). Arthralgia (41,4% vs 25%, p = 0.02) and pain at injection (51,4% vs 27%, p = 0.001) were more common with ChAdOx1. No serious AEs were related. With Regard to RA activity level, no significant difference was observed between the three time periods for both COVID-19 vaccines. CONCLUSION: In the comparison between the two immunizers in patients with RA, local reactions and musculoskeletal symptoms were more frequent with ChAdOx1 than with CoronaVac, especially after the first dose. In summary, the AE occurred mainly after the first dose, and were mild, like previous data from others immunizing agents in patients with rheumatoid arthritis. Vaccination did not worsen the degree of disease activity.

Recommendations on cutaneous and hematological manifestations of Sjögren's disease by the Brazilian Society of Rheumatology.

Sjogren's disease (SjD) is an autoimmune disease that is characterized not only by the sicca symptoms it causes but also by its systemic nature, which is capable of several and not yet fully understood extraglandular manifestations. To gain a clearer understanding of these manifestations as well as a better practical approach, a panel of experts from the Brazilian Society of Rheumatology conducted a systematic review and meta-analysis on the identification of epidemiologic and clinical features of the extraglandular manifestations present in ESSDAI (EULAR Sjogren´s syndrome disease activity index), followed by a voting panel with recommendations for clinical practice. This publication is complementary to others already published and covers cutaneous and hematological manifestations, with prevalence data generated by a meta-analysis of 13 clinical or laboratory manifestations and 6 clinical management recommendations.

High Adherence to the Mediterranean Dietary Pattern Is Inversely Associated with Systemic Inflammation in Older but Not in Younger Brazilian Adults.

The Mediterranean dietary pattern (MPD) has shown promise in preventing low-grade systemic inflammation (LGSI). This study tested if a high adherence to the MDP by younger and older Brazilian adults is associated with lower LGSI and investigated which Mediterranean food components may contribute to these associations. We performed a secondary study on 2015 ISA-Nutrition (290 younger adults (20-59 years old) and 293 older adults (≥60 years old)), a cross-sectional population-based study in São Paulo, SP, Brazil. The adherence to the MDP was assessed using the Mediterranean Diet Score (MedDietScore), obtained from two non-consecutive 24 h dietary recalls (24HDRs). The LGSI score (from plasma CRP, TNF-α, and adiponectin) identified the inflammatory status. Linear regression models assessed the association between LGSI and the MedDietScore. In older adults only, a high adherence to the MDP signified an 11.5% lower LGSI score. Older adults, classified with high adherence to the MDP, differed by consuming lower meat intake and full-fat dairy. Between older adults, the intake of vegetables and olive oil was inversely associated with the levels of LGSI. Thus, among older adults, the intake of some specific Mediterranean food determined high adherence to the MDP and was associated with decreased LGSI.

Evaluating the influence of ultra-processed food intake on associations between dietary indices with systemic inflammation in adulthood and old ages.

BACKGROUND & AIMS: Low-grade systemic inflammation (LGSI) is critical to developing many chronic diseases. In turn, it has been shown that the diet can modulate favorably or unfavorably the inflammatory status. Thus, evaluating the diet from appropriate approaches is fundamental; to do so, there are different proposals for dietary indexes. We aimed to: (i) investigate the association between three well-known dietary indexes and LGSI biomarkers; (ii) test these associations individually or in combination with an indicator of ultra-processed foods (UFPs) intake. (iii) as an additional aim, hypothesizing that all the indexes should be capable of identifying the inflammatory potential of diet, we tested the hypothesis that these indexes agree and correlate with each other. METHODS: Cross-sectional population-based data of adults and older persons (n = 583). Dietary data were obtained through two non-consecutive 24-h dietary recalls (24HDR) and calculated for Dietary Inflammatory Index (DII), Mediterranean-Style Dietary Pattern Score (MSDPS); Brazilian Healthy Eating Index - Revised (BHEI-R) and energy ingested from UPFs (UPFs ratio). An LGSI score was created from some plasma inflammatory biomarkers [C-Reactive Protein (CRP), tumor necrosis factor-alpha (TNF-α), and adiponectin]. Logistic and linear regression models tested the associations between dietary indexes and LGSI score. RESULTS: The MSDPS and DII were significantly associated with our inflammatory score, but the BHEI-R did not. Including UPFs in regression models did not increase the strength of these associations. CONCLUSIONS: From the three scores, the dietary inflammatory index and the Mediterranean-style dietary pattern score (MSDPS) were the ones that showed significant association with the inflammatory biomarker. The combination of the indexes with a ratio of UPF intake did not increase the significance of our analyses. The best agreement between the indexes was found between MSDPS and UPFs ratio; the only pair of indexes considered concordant and correlated was the BHEI-R and DII.

To be or not to B27 positive: implications for the phenotypes of axial spondyloarthritis outcomes. Data from a large multiracial cohort from the Brazilian Registry of Spondyloarthritis.

BACKGROUND: There is a remarkable variability in the frequency of HLA-B27 positivity in patients with spondyloarthritis (SpA), which may be associated with different clinical presentations worldwide. However, there is a lack of data considering ethnicity and sex on the evaluation of the main clinical and prognostic outcomes in mixed-race populations. The aim of this study was to evaluate the frequency of HLA-B27 and its correlation with disease parameters in a large population of patients from the Brazilian Registry of Spondyloarthritis (RBE). METHODS: The RBE is a multicenter, observational, prospective cohort that enrolled patients with SpA from 46 centers representing all five geographic regions of Brazil. The inclusion criteria were as follow: (1) diagnosis of axSpA by an expert rheumatologist; (2) age ≥18 years; (3) classification according to ASAS axial. The following data were collected via a standardized protocol: demographic data, disease parameters and treatment historical. RESULTS: A total of 1096 patients were included, with 73.4% HLA-B27 positivity and a mean age of 44.4 (±13.2) years. Positive HLA-B27 was significantly associated with male sex, earlier age at disease onset and diagnosis, uveitis, and family history of SpA. Conversely, negative HLA-B27 was associated with psoriasis, higher peripheral involvement and disease activity, worse quality of life and mobility. CONCLUSIONS: Our data showed that HLA-B27 positivity was associated with a classic axSpA pattern quite similar to that of Caucasian axSpA patients around the world. Furthermore, its absence was associated with peripheral manifestations and worse outcomes, suggesting a relevant phenotypic difference in a highly miscegenated population.

Path analysis of urinary incontinence in older adults living in nursing homes / Fatores associados à incontinência urinária em idosos institucionalizados

Objective: To investigate the factors associated with urinary incontinence in older adults living in nursing homes. Methods: This was an exploratory, cross-sectional, observational, and quantitative study using exploratory and path analysis (PA). Eighty-six older adults living in nursing homes in the city of Salvador, Brazil, and the city of Brasília, Brazil, were included. Data were collected from January to March 2020, before the Covid-19 pandemic. The following variables were evaluated: sex, age group, functional performance, global cognitive function, comorbidities, and health conditions. Results: Urinary incontinence was associated with educational level, marital status, hypertension, one or more difficulties in basic activities of daily living, mood, insomnia, loss of appetite, fecal incontinence, and difficulty swallowing. In the PA, depression and difficulty swallowing were directly associated with urinary incontinence, and urinary incontinence was directly and significantly associated with insomnia and fecal incontinence. Conclusion: Given the variety of social and health components associated with urinary incontinence, it is necessary to assess, prevent, treat, and rehabilitate this condition in Brazilian nursing homes. Interventions in urinary incontinence demand integrated actions in functional, clinical, and mental health aspects to promote the well-being of older adults living in nursing homes. (AU)

Objetivo: Investigar os fatores associados à incontinência urinária em pessoas idosas institucionalizadas segundo a Análise de Caminhos. Metodologia: Trata-se de um estudo transversal. Foram avaliados 86 idosos em Instituições de Longa Permanência para Idosos brasileiras de Salvador (BA) e Brasília (DF), no período entre janeiro e março de 2020, período pré-pandemia de COVID-19. Os fatores analisados incluíram: sexo, faixa etária, desempenho funcional, desempenho cognitivo global, comorbidades e condições de saúde. Resultados: Observou-se que a incontinência urinária esteve associada ao nível de escolaridade, estado civil, hipertensão, uma ou mais dificuldades nas atividades básicas da vida diária, humor, insônia, perda de apetite, incontinência fecal e dificuldade de deglutição. Na Análise de Caminhos, os sintomas depressivos e as dificuldades de deglutição tiveram associação direta com a incontinência urinária, e a incontinência urinária teve associação direta e significativa com a insônia e a incontinência fecal. Conclusão: Dada a variedade de componentes sociais e de saúde associados à incontinência urinária, é necessário avaliar, prevenir, recuperar e reabilitar essa condição nas Instituições de Longa Permanência para Idosos brasileiras. Intervir na incontinência urinária requer ações integradas nos aspectos funcionais, clínicos e de saúde mental, que podem favorecer o bem-estar das pessoas idosas institucionalizadas. (AU)

Dietary Inflammatory Index of Obese Individuals with Obstructive Sleep Apnea: A Descriptive Study.

The objective of the present study was to describe the dietary inflammatory profile and its correlations with sleep parameters of obese individuals with obstructive sleep apnea (OSA). Forty individuals underwent nocturnal polysomnography, anthropometric measurements, body composition by plethysmography, assessment of food consumption by three-day food records, and blood collection for the lipid, glycemic and hormonal profile. Food consumption data were evaluated semiquantitatively, quantitalively assessment, and calculation of the dietary inflammatory index (DII) was perfomed. The results demonstrated a predominantly proinflammatory dietary profile. The participants showed a low intake of fruit and vegetables. Additionally, a low consumption of fiber, magnesium, vitamin D, and vitamin E was observed, although there was an adequate distribution of macronutrients. In conclusion, although the inflammatory profile did not correlate with OSA, the study showed a directly proportional relationship between adequate dietary patterns and better sleep quality.

Gut microbiota disturbances in hospitalized older adults with malnutrition and clinical outcomes.

OBJECTIVE: Malnutrition is one of the most threatening conditions in geriatric populations. The gut microbiota has an important role in the host's metabolic and muscular health: however, its interplay with disease-related malnutrition is not well understood. We aimed to identify the association of malnutrition with the gut microbiota and predict clinical outcomes in hospitalized acutely ill older adults. METHODS: We performed a secondary longitudinal analysis in 108 geriatric patients from a prospective cohort evaluated at admission and 72 h of hospitalization. We collected clinical, demographic, nutritional, and 16S rRNA gene-sequenced gut microbiota data. Microbiota diversity, overall composition, and differential abundance were calculated and compared between patients with and without malnutrition. Microbiota features associated with malnutrition were used to predict clinical outcomes. RESULTS: Patients with malnutrition (51%) had a different microbiota composition compared to those who were well-nourished during hospitalization (ANOSIM R = 0.079, P = 0.003). Patients with severe malnutrition showed poorer α-diversity at admission (Shannon P = 0.012, Simpson P = 0.018) and follow-up (Shannon P = 0.023, Chao1 P = 0.008). Differential abundance of Lachnospiraceae NK4A136 group, Subdoligranulum, and Faecalibacterium prausnitzii were significantly lower and inversely associated with malnutrition, while Corynebacterium, Ruminococcaceae Incertae Sedis, and Fusobacterium were significantly increased and positively associated with malnutrition. Corynebacterium, Ruminococcaceae Incertae Sedis, and the overall composition were important predictors of critical care in patients with malnutrition during hospitalization. CONCLUSION: Older adults with malnutrition, especially in a severe stage, may be subject to substantial gut microbial disturbances during hospitalization. The gut microbiota profile of patients with malnutrition might help us to predict worse clinical outcomes.

Sarcopenia risk, sarcopenia-related quality of life, and associated factors in people living with human immunodeficiency virus (HIV): A web-based survey.

OBJECTIVES: We aimed to screen for the risk of sarcopenia and sarcopenia-related quality of life and associated factors of people living with HIV (PLWH). RESEARCH METHODS AND PROCEDURES: This nonprobabilistic web-based survey evaluated PLWH. The participants were invited directly from a university-based inpatient clinic and responded to a web questionnaire that included the SARC-F and SarQoL to screen people at risk of sarcopenia and their quality of life. People at risk of sarcopenia were defined by the proposed cutoff points for SARC-F (≥ 4 points), and SarQoL overall score was categorized according to the median. Moreover, we performed a logistic regression to investigate associations between HIV-, lifestyle-, and health-associated factors (i.e., physical activity, dietary pattern, sleep quality, gastrointestinal symptoms, HIV diagnosis, type, combinations, and duration of ART, smoking, drinking, BMI, and weight loss), and outcomes (SARC-F and SarQoL). RESULTS: The sample comprised 202 PLWH, mainly middle-aged (50.6-60.5 y; n = 101). Only 5.9% (n = 12) are at risk of sarcopenia according to SARC-F, and only 17.3% (n = 35) exhibited lower sarcopenia-related quality of life according to SarQoL. In the multiple models, only the gastrointestinal symptoms increased the odds of sarcopenia risk (OR: 1.058; P = 0.01) and poor sarcopenia-associated quality of life (OR: 1.041; P = 0.013). CONCLUSIONS: We verified that only 5.9% and 17.3% of PLWH are at risk of sarcopenia and presented lower sarcopenia-related quality of life, respectively. Only the gastrointestinal symptoms were associated with a risk of sarcopenia and lower sarcopenia-related quality of life, without significant differences between age groups.

Nest-building in breeding mice: Impact of macro- and micro-environment.

The housing conditions of laboratory mice must be strictly controlled in order to reduce the impact of pathophysiological changes that affect animal health and welfare, possibly resulting in increased variability within experimental results. One way to improve the activity and survival of laboratory mice is to provide nesting material. The objective of this study was to determine if nest-building quality could be used to detect changes in murine mating behaviour in a rodent facility under controlled conditions. Nesting scores of 847 cages with monogamous pairs from three different genetic backgrounds (129, B6 and BALB/c) of both sexes were correlated with 18 predefined variables. The effects on nest quality were evaluated using descriptive data analysis, correspondence analysis and ordinal logistic model fitting. The results showed a strong relationship between nest quality and nest position. Humidity, genetic background, cage change and the number and age of pups in the cage affected the nest-building scores. The most important indicators were cage change and relative humidity, both of which exerted significant negative effects on nest-building quality. Even though the criteria were well defined, the observer could still influence nest score appraisal. However, in a long-term observational study, observers could improve their assessment by training and acquiring greater experience in score assignment. Nest-building scores are easy to assess in the cage, with little discomfort to the animal. Moreover, the nest score is a valid indicator of the health and well-being of laboratory mice and can provide valuable support in the management of animal facilities.

Factors Associated With Mortality in Patients With Immune-Mediated Rheumatic Diseases and COVID-19 From Latin America: Data From Argentina, Mexico, and Brazil.

OBJECTIVE: To describe characteristics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in patients with rheumatic immune-mediated inflammatory diseases (IMIDs) from Argentina, Mexico and Brazil, and to assess factors associated with mortality in this population. METHODS: Data from 3 national registries, SAR-COVID (Argentina), CMR-COVID (Mexico), and ReumaCoV-Brasil (Brazil), were combined. Adult patients with IMIDs and SARS-CoV-2 infection were recruited. Sociodemographic data, comorbidities, IMID clinical characteristics and treatment, and SARS-CoV-2 infection presentation and outcomes were recorded. RESULTS: A total of 4827 individuals were included: 2542 (52.7%) from SAR-COVID, 1167 (24.2%) from CMR-COVID, and 1118 (23.1%) from ReumaCoV-Brasil. Overall, 82.1% were female with a mean age of 49.7 (SD, 14.3) years; 22.7% of the patients were hospitalized, and 5.3% died because of COVID-19 (coronavirus disease 2019). Argentina and Brazil had both 4% of mortality and Mexico 9.4%. In the multivariable analysis, older age (≥60 years; odds ratio [OR], 7.4; 95% confidence interval [CI], 4.6-12.4), male sex (OR, 1.5; 95% CI, 1.1-2.1), living in Mexico (OR, 3.0; 95% CI, 2.0-4.4), comorbidity count (1 comorbidity: OR, 1.5; 95% CI, 1.0-2.1), diagnosis of connective tissue disease or vasculitis (OR, 1.8; 95% CI, 1.3-2.4), and other diseases (OR, 2.6; 95% CI, 1.6-4.1) compared with inflammatory joint disease, high disease activity (OR, 4.2; 95% CI, 2.5-7.0), and treatment with glucocorticoids (OR, 1.9; 95% CI, 1.4-2.5) or rituximab (OR, 4.2; 95% CI, 2.7-6.6) were associated with mortality. CONCLUSIONS: Mortality in patients with IMIDs was particularly high in Mexicans. Ethnic, environmental, societal factors, and different COVID-19 mitigation measures adopted have probably influenced these results.

Impact of Risk Factors on COVID-19 Outcomes in Unvaccinated People With Rheumatic Diseases: A Comparative Analysis of Pandemic Epochs Using the COVID-19 Global Rheumatology Alliance Registry.

OBJECTIVE: Approximately one third of individuals worldwide have not received a COVID-19 vaccine. Although studies have investigated risk factors linked to severe COVID-19 among unvaccinated people with rheumatic diseases (RDs), we know less about whether these factors changed as the pandemic progressed. We aimed to identify risk factors associated with severe COVID-19 in unvaccinated individuals in different pandemic epochs corresponding to major variants of concern. METHODS: Patients with RDs and COVID-19 were entered into the COVID-19 Global Rheumatology Alliance Registry between March 2020 and June 2022. An ordinal logistic regression model (not hospitalized, hospitalized, and death) was used with date of COVID-19 diagnosis, age, sex, race and/or ethnicity, comorbidities, RD activity, medications, and the human development index (HDI) as covariates. The main analysis included all unvaccinated patients across COVID-19 pandemic epochs; subanalyses stratified patients according to RD types. RESULTS: Among 19,256 unvaccinated people with RDs and COVID-19, those who were older, male, had more comorbidities, used glucocorticoids, had higher disease activity, or lived in lower HDI regions had worse outcomes across epochs. For those with rheumatoid arthritis, sulfasalazine and B-cell-depleting therapy were associated with worse outcomes, and tumor necrosis factor inhibitors were associated with improved outcomes. In those with connective tissue disease or vasculitis, B-cell-depleting therapy was associated with worse outcomes. CONCLUSION: Risk factors for severe COVID-19 outcomes were similar throughout pandemic epochs in unvaccinated people with RDs. Ongoing efforts, including vaccination, are needed to reduce COVID-19 severity in this population, particularly in those with medical and social vulnerabilities identified in this study.

NAGPKin: Nucleation-and-growth parameters from the kinetics of protein phase separation.

The assembly of biomolecular condensate in eukaryotic cells and the accumulation of amyloid deposits in neurons are processes involving the nucleation and growth (NAG) of new protein phases. To therapeutically target protein phase separation, drug candidates are tested in in vitro assays that monitor the increase in the mass or size of the new phase. Limited mechanistic insight is, however, provided if empirical or untestable kinetic models are fitted to these progress curves. Here we present the web server NAGPKin that quantifies NAG rates using mass-based or size-based progress curves as the input data. A report is generated containing the fitted NAG parameters and elucidating the phase separation mechanisms at play. The NAG parameters can be used to predict particle size distributions of, for example, protein droplets formed by liquid-liquid phase separation (LLPS) or amyloid fibrils formed by protein aggregation. Because minimal intervention is required from the user, NAGPKin is a good platform for standardized reporting of LLPS and protein self-assembly data. NAGPKin is useful for drug discovery as well as for fundamental studies on protein phase separation. NAGPKin is freely available (no login required) at https://nagpkin.i3s.up.pt.

New insights at the interface between leprosy and immune-mediated rheumatic diseases.

Leprosy is an infectious and contagious disease of slow evolution, triggered by Mycobacterium leprae. Arthritis is its third most common manifestation, after cutaneous and peripheral nerve involvement. Since musculoskeletal symptoms may be the initial presentation of the disease, it is important for health professionals to recognize its rheumatic manifestations for early diagnosis and appropriate treatment, especially in endemic areas. In addition, cases of leprosy have increased globally, notably in patients undergoing treatment with TNF-α blockers and due to the increase in migration and travel of people from developing countries to developed countries. This review proposes to discuss the main scenarios of mimicry of different rheumatic diseases by leprosy, as well as the role of immunosuppressive drugs used in rheumatology practice in the treatment of reactional states and in the risk of developing the infection.

Drug repurposing of dopaminergic drugs to inhibit ataxin-3 aggregation.

The accumulation of mutant ataxin-3 (Atx3) in neuronal nuclear inclusions is a pathological hallmark of Machado-Joseph disease (MJD), also known as Spinocerebellar Ataxia Type 3. Decreasing the protein aggregation burden is a possible disease-modifying strategy to tackle MJD and other neurodegenerative disorders for which only symptomatic treatments are currently available. We performed a drug repurposing screening to identify inhibitors of Atx3 aggregation with known toxicological and pharmacokinetic profiles. Interestingly, dopamine hydrochloride and other catecholamines are among the most potent inhibitors of Atx3 aggregation in vitro. Our results indicate that low micromolar concentrations of dopamine markedly delay the formation of mature amyloid fibrils of mutant Atx3 through the inhibition of the earlier oligomerization steps. Although dopamine itself does not cross the blood-brain barrier, dopamine levels in the brain can be increased by low doses of dopamine precursors and dopamine agonists commonly used to treat Parkinsonian symptoms. In agreement, treatment with levodopa ameliorated motor symptoms in a C. elegans model of MJD. These findings suggest a possible application of dopaminergic drugs to halt or reduce Atx3 accumulation in the brains of MJD patients.

Pathogen-specific structural features of Candida albicans Ras1 activation complex: uncovering new antifungal drug targets.

An important feature associated with Candida albicans pathogenicity is its ability to switch between yeast and hyphal forms, a process in which CaRas1 plays a key role. CaRas1 is activated by the guanine nucleotide exchange factor (GEF) CaCdc25, triggering hyphal growth-related signaling pathways through its conserved GTP-binding (G)-domain. An important function in hyphal growth has also been proposed for the long hypervariable region downstream the G-domain, whose unusual content of polyglutamine stretches and Q/N repeats make CaRas1 unique within Ras proteins. Despite its biological importance, both the structure of CaRas1 and the molecular basis of its activation by CaCdc25 remain unexplored. Here, we show that CaRas1 has an elongated shape and limited conformational flexibility and that its hypervariable region contains helical structural elements, likely forming an intramolecular coiled-coil. Functional assays disclosed that CaRas1-activation by CaCdc25 is highly efficient, with activities up to 2,000-fold higher than reported for human GEFs. The crystal structure of the CaCdc25 catalytic region revealed an active conformation for the α-helical hairpin, critical for CaRas1-activation, unveiling a specific region exclusive to CTG-clade species. Structural studies on CaRas1/CaCdc25 complexes also revealed an interaction surface clearly distinct from that of homologous human complexes. Furthermore, we identified an inhibitory synthetic peptide, prompting the proposal of a key regulatory mechanism for CaCdc25. To our knowledge, this is the first report of specific inhibition of the CaRas1-activation via targeting its GEF. This, together with their unique pathogen-structural features, disclose a set of novel strategies to specifically block this important virulence-related mechanism. IMPORTANCE Candida albicans is the main causative agent of candidiasis, the commonest fungal infection in humans. The eukaryotic nature of C. albicans and the rapid emergence of antifungal resistance raise the challenge of identifying novel drug targets to battle this prevalent and life-threatening disease. CaRas1 and CaCdc25 are key players in the activation of signaling pathways triggering multiple virulence traits, including the yeast-to-hypha interconversion. The structural similarity of the conserved G-domain of CaRas1 to those of human homologs and the lack of structural information on CaCdc25 has impeded progress in targeting these proteins. The unique structural and functional features for CaRas1 and CaCdc25 presented here, together with the identification of a synthetic peptide capable of specifically inhibiting the GEF activity of CaCdc25, open new possibilities to uncover new antifungal drug targets against C. albicans virulence.

The dopaminergic D1 receptor modulates the hyperactivity of Bapa mutant mice.

The mutant bate-palmas ("claps"; symbol - bapa) mice induced by the mutagenic chemical ENU present motor incoordination and postural alterations. A previous study showed that bapa mice present increased motor/exploratory behaviors during the prepubertal period due to increased striatal tyrosine hydroxylase expression, suggesting striatal dopaminergic system hyperactivity. This study aimed to evaluate the involvement of striatal dopaminergic receptors in the hyperactivity of bapa mice. Male bapa mice and their wild strain (WT) were used. Spontaneous motor behavior was observed in the open-field test, and stereotypy was evaluated after apomorphine administration. The effects of DR1 and DR2 dopaminergic antagonists (SCH-23,390; sulpiride) and the striatal DR1 and D2 receptor gene expression were evaluated. Relative to WT, bapa mice showed: 1) increased general activity for four days; 2) increased rearing and sniffing behavior and decreased immobility after apomorphine; 3) blockage of rearing behavior after the DR2 antagonist but no effect after DR1 antagonist; 4) blockage of sniffing behavior after the DR1 antagonist in bapa and WT mice but no effect after the DR2 antagonist; 5) increased immobility after the DR1 antagonist but no effect after the DR2 antagonist; 6) increased expression of striatal DR1 receptor gene and reduced the DR2 expression gene after apomorphine administration. Bapa mice showed increased activity in open field behavior. The increased rearing behavior induced by apomorphine of bapa mice resulted from the increased gene expression of the DR1 receptor.

Evaluation of the dietary inflammatory index in children and adolescents with type 1 diabetes mellitus and its relationship with nutritional status and metabolic control.

OBJECTIVES: The aim of this study was to evaluate the association of the dietary inflammatory index (DII) with the nutritional status and metabolic control of children and adolescents with type 1 diabetes mellitus. METHODS: This was a cross-sectional study that examined data of children and adolescents ages 7 to 16 y diagnosed with type 1 diabetes mellitus. Dietary intake was assessed using a 24-h dietary recall, from which the DII was calculated. The outcomes were body mass index, lipid profiles (low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol), and glycated hemoglobin. The DII was evaluated in tertiles and in a continuous way. Multiple linear regression was adopted in the analysis, with P < 0.05 considered significant. RESULTS: Overall, 120 children and adolescents with a mean age of 11.7 (± 2.8) y were included, 53.3% (n = 64) of whom were girls. Excess weight was present in 31.7% participants (n = 38). The average DII was +0.25, ranging from -1.11 to +2.67. Higher values of selenium (P = 0.011), zinc (P = 0.001), fiber (P < 0.001), and other micronutrients were observed in the first tertile of the DII (diet with more antiinflammatory potential). The DII appeared as a predictor of body mass index (P = 0.002; ß = 0.23; 95% confidence interval [CI], 0.39-1.75) and non-high-density lipoprotein cholesterol (P = 0.034; ß = 0.19; 95% CI, -13.5 to 0.55). There was a tendency for DII to be associated with glycemic control (P = 0.09; ß = 0.19; 95% CI, -0.04 to 0.51). CONCLUSIONS: The inflammatory potential of the diet was associated with increased body mass index and aspects related to metabolic control in children and adolescents with type 1 diabetes mellitus.